Year: 2024
Type: article
Abstract: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, repetitive behaviors, and restricted interests [1]. ASD is associated with a broad range of concomitant conditions, with epilepsy being one of the most significant and frequent [2,3]. Although ASD and epilepsy exhibit different symptoms and underlying causes [4], there is a strong relationship in their physical and cognitive manifestations [4,5], as confirmed by the fact that up to 30% of individuals with ASD may have epilepsy [6].In a recent meta-analysis, a comprehensive exploration of seventy-three studies delved into the point prevalence of active epilepsy, ultimately distilling 67 estimates from 63 unique studies for inclusion in the meta-analysis [6,7]. The resultant synthesis revealed a pooled point prevalence of active epilepsy standing at 6.38 per 1,000 persons [7]. Shifting focus to the USA, several population-based studies in the pediatric realm uncovered a notably higher incidence of epilepsy within the first year of life, ranging from 82.1 to 118 per 100,000 person-years, eclipsing the rate observed in older children, which hovered around 46 per 100,000 person-years. An additional prospective study mirrored this trend, recording an incidence of 75 per 100,000 live births before 6 months and 62 per 100,000 between 6 and 12 months-an unprecedented revelation that diverges significantly from previously published estimates [8]. Beyond point prevalence, twelve studies contributed insights into the annual prevalence of active epilepsy [9]. The pooled outcome showcased an annual prevalence of 2.83 per 1,000 persons, while the median annual prevalence charted at 3.91 per 1,000 persons [10]. Nestled within this complex tapestry of prevalence, the pediatric population grappling with both ASD and epilepsy emerges as a multifaceted, multidimensional conundrum. This intricate landscape unfolds against a backdrop of diverse symptoms, genetic foundations, and clinical expressions [11]. ASD and epilepsy embark on an evolutionary journey from childhood to adulthood, casting a growing therapeutic demand that resonates not only with patients and their families but reverberates within educational systems and society at large [11,12].Delving into the realm of seizures, their classification unfolds into episodes characterized by either motor or non-motor symptoms-a spectrum encompassing generalized tonicclonic seizures, clonic seizures, tonic seizures, and myoclonic seizures [13][14][15]. Typical absences manifest with a sudden onset, interrupting ongoing activities, featuring a fixed gaze, unresponsiveness to speech, and a duration spanning seconds to half a minute, culminating in a swift recovery [16]. Crucially, it's paramount to underscore that the term "absence" doesn't equate to a fixed gaze, as this characteristic may also manifest in focal onset seizures [17]. In contrast, atypical absence displays more pronounced changes in tone compared to typical absence, marked by a non-abrupt onset or termination.Myoclonic absence introduces a sudden, brief (< 100 ms), involuntary, non-repetitive, and non-sustained contraction with associated absence. Adding another layer to this intricate spectrum, absence with eyelid myoclonia involves eyelid jerks occurring at a frequency of less than 3 per second, often with eyes deviated upward, typically lasting less than 10 seconds. This phenomenon is frequently triggered by eye closure and bears a high likelihood of photosensitivity [18].In 2017, the ILAE Epilepsy Classification unfurled three diagnostic levels [15], enriching our understanding of this intricate landscape. The first level takes root in the seizure type, encompassing an expansive array of concepts-be they focal, generalized, or of unknown onset. This level also introduces two pivotal concepts woven into the diagnostic fabric: comorbidity (associated pathological entities) and etiology. Some patients may find a resting place at this diagnostic level due to investigational limitations, either as a valid endpoint or as the precursor in their diagnostic journey [19]. Stepping into the second diagnostic level, the scene unfolds when at least one EEG and brain imaging study graces the diagnostic landscape. Here, the focus shifts to determining the type of epilepsyfocal, generalized, combined (merging both focal and generalized seizures, a common theme in various epileptic syndromes), or of unknown origin. Etiological diagnoses cast their net into structural, genetic, infectious, metabolic, immune, or unknown categories [20]. In the intricate dance of medical complexities, a patient may wear more than one etiological hat. For instance, a patient with tuberous sclerosis might proudly display cortical tubers, embodying both a structural and genetic etiology [21]. The final frontier, the third diagnostic level, immerses us in the realm of epileptic syndromes-a composite tapestry weaving together common characteristics such as seizure types, specific EEG findings, age-dependent imaging features, onset and remission age, specific triggering factors, daily variations, prognosis nuances, and distinctive intellectual and psychiatric comorbidities. It's a canvas where etiological and treatment implications unfurl their tales [22,23]. This paradigm-shifting classification boldly swaps out the term "benign" for the more apt descriptors "self-limited" or "drug-responsive." The unfolding narrative beckons further exploration and inquiry into the ever-evolving lexicon of epilepsy classification.Regarding ASD, there is significant interindividual clinical variability. Within families, it has been indicated that both genetic and environmental factors influence the phenotypic expression of ASD [12,13]. Many of the core or nuclear symptoms, while reduced to deficits in social communication and interaction and repetitive or stereotyped behaviors, do not manifest their extensive symptomatic expression [10][11][12][13].The neural pathways proposed as the biological basis in ASD associated with epilepsy are related to: 1) imbalance between the glutamatergic (excitatory) and GABAergic (inhibitory) pathways; 2) alteration in the cholinergic pathway; and 3) disruption in synaptic plasticity and oxidative stress [23].ASD and epilepsy are associated with a high level of psychiatric comorbidity, including anxiety, self or hetero-aggression, depression, hyperactivity, obsessive-compulsive disorder, attention difficulties, tics, eating disorders, executive function impairment, and sleep disorders, which may require pharmacological therapy at some stage of evolution, as well as other relevant symptoms [24], highlighted in the following Table 1: [24] and Boesen et al. [25] There are commonly other comorbidities related to severe neurological alterations. A well-studied example of which association between ASD and epilepsy is tuberous sclerosis, in which infantile epileptic spasms appear to be a risk factor for ASD regardless of the location and number of brain tubers [26]. All of this is related to the fact that, during the ontogenesis of the nervous system, certain brain areas mature chronologically before others, following a genetically determined program [27]. If this maturation process is interfered with by frequent seizures, the consequences can be serious for the consolidation of emerging cognitive functions and the development of the social brain [28]. Moreover, epileptiform discharges can occur in the absence of clinical seizures but still impact the brain's maturation process [29]. Therefore, tuberous sclerosis represents one of the most attractive etiopathogenic models-genetic, biochemical, structural, and neurophysiological-to understand the bidirectional interaction between ASD and epilepsy [27].Considering this information, the main objective of this opinion article is to discuss and update the primary pharmacological and surgical treatments for the care of the pediatric population diagnosed with ASD and epilepsy.The pharmacological treatment choice in the pediatric population with ASD and epilepsy is complex and requires an interdisciplinary approach. Specialists in neurology, pediatrics, and psychiatry must design a personalized treatment plan to address the child's needs [28].As mentioned earlier, the comorbidity of ASD and epilepsy presents a wide range of associated symptoms in individuals [29]. The pharmacological care for this population becomes significantly complex. Many experts recommend treatment plan begins with the management of ASD-related symptoms using medications that help reduce or alleviate these symptoms [30]. Several studies refer to the administration of drugs such as antipsychotics or antidepressants to address the semiological characteristics that appear in this disorder [31]. Table 2 provides a list of the most common alterations in ASD and their pharmacological treatment. Medications administered for psychiatric symptoms work by reducing or preventing abnormal electrical activity in the brain that leads to seizures. Currently, there are different drugs available, and their selection depends on the type of seizure, the child's age, and comorbid conditions [32][33][34][35]. In cases where a person with ASD does not experience seizures, the administration of medications to address psychiatric symptoms will focus on addressing behavioral, emotional, or cognitive aspects associated with ASD. These medications may be prescribed to manage issues such as anxiety, hyperactivity, aggression, sleep disorders, or other psychiatric symptoms that may arise in individuals with ASD. The choice of medication will depend on the specific nature of the symptoms and the assessment by the healthcare professional. Medications administered for psychiatric symptoms associated with ASD are often used in combination with other types of medications such as anxiolytics, antipsychotics, and antidepressants, depending on the epileptic symptoms and the severity of the epilepsy episodes the person is experiencing [35]. Table 3 details the main drugs for treating epilepsy based on the symptoms presented by individuals with ASD and epilepsy. Focal, focal to bilateral tonic clonic, generalized tonic clonic, and myoclonic Another significant challenge is the high interaction among the drugs described above [26][27][28][29][30][31][32][33][34][35][36][37]. Antipsychotic drugs have significant reactions and drug interactions with anticonvulsants and mood stabilizers, including carbamazepine, though not all of these interactions occur negatively [38,39]. Identifying the consequences of such combinations is highly relevant, as, in some cases, serious adverse reactions may develop. This is exemplified by De León et al.'s [40] of interactions between anti-seizure medicines (ASMs) and second-generation antipsychotics potentially leading to exceptional cases of pancreatitis, agranulocytosis/leukopenia, and heatstroke. Additionally, Hitchings [41], in a review study, suggests that antipsychotics, by reducing the antiepileptic effect of these drugs, may reduce the efficacy of anti-seizure drugs.Clozapine, known for reducing the seizure threshold, is linked to dose-dependent electroencephalographic alterations, impacting approximately 3-6% of patients under clozapine treatment. risperidone paired with lithium or valproate, and quetiapine combined with lithium or valproate [43]. The simultaneous administration of these medications should be approached with caution due to the potential emergence of toxic symptoms at high doses.Moreover, acute manic symptoms, extrapyramidal effects, physiological disorders, or brain damage could manifest, altering the neurological structure in which the epilepsy focus is located [44][45][46].Medical treatments for ASD and epilepsy typically focus on managing the core symptoms of both disorders (ASD and epilepsy), addressing concurrent physical conditions such as sleep disorders, gastrointestinal issues, and sensory difficulties [47]. However, unresolved issues persist in understanding the comorbidity between ASD and epilepsy. One fundamental challenge lies in the relationship between seizures and the central social symptoms of ASD. Although there is a high prevalence of epilepsy in individuals with ASD, the exact nature of how seizures contribute to the social aspects of ASD remains an actively researched area. Significant variability in the frequency of seizures also raises questions. While some children with ASD and epilepsy experience recurrent episodes, others may have a single episode in their lifetime. This variability not only complicates the understanding of the relationship between seizures and ASD but also presents challenges in identifying predictive patterns and personalized treatment strategies.Epilepsy itself represents a significant clinical problem, but the decision to resort to surgery must be approached with caution and is reserved for cases of refractory epilepsy with clearly defined cortical abnormalities that require surgical intervention [48]. This decision entails the need for an accurate diagnosis and the identification of suitable candidates for surgical procedures, which remains an area in development. The comorbidity between ASD and epilepsy remains an unresolved clinical issue, exacerbated by a substantial lack of data and the complexity of interactions between both disorders [49]. Ongoing research is essential to unravel the underlying mechanisms, better understand the variability in clinical presentation, and develop more effective and personalized treatment approaches for those affected by this comorbidity [50].Upon receiving a referral, it is customary for the patient to undergo a thorough preoperative evaluation with the aim of identifying the epileptogenic zone and evaluating the patient's suitability for surgery [51]. This evaluation typically includes a detailed medical history (analyzing clinical semiology, seizure frequency, severity, and prior treatments), video electroencephalography (EEG), magnetic resonance imaging (MRI) using an epilepsy protocol, and neuropsychological testing [52]. Depending on the clinical context, additional tests such as positron emission tomography, single-photon emission computed tomography, magnetoencephalography, functional magnetic resonance imaging, and Wada testing may be considered [52,53]. The results of these assessments are then reviewed by a multidisciplinary team, which provides treatment recommendations. In certain cases, supplementary information is gathered through the surgical placement of intracranial electrodes to enhance the localization of the epileptogenic focus and identify critical brain areas for preservation during surgery [53].For focal-onset seizures that can be localized in a surgically manageable area, available options encompass lesionectomy, temporal lobectomy, or extratemporal cortical resection. These procedures may be executed as a single intervention or in two stages, occasionally preceded by invasive EEG monitoring [54]. 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Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,125
OpenAlex ID: W4392082014